Serum levels of high-density lipoprotein cholesterol (HDL-C) are a
widely validated predictor of risk for cardiovascular (CV) disease in both men
and women.1,2 Low levels of
HDL-C are associated with increased risk for CV events, including stroke,
nonfatal myocardial infarction (MI) and death, while high levels portend lower
risk for these clinical endpoints. A number of meta-analyses have suggested
that use of statin therapy to elevate HDL-C contributes to the capacity of the
statin drugs to reduce risk both for coronary artery disease (CAD) progression
and for acute CV events.3-5 Important post hoc analyses from the Air Force/Texas
Coronary Atherosclerosis Prevention Study6 and
Bezafibrate Infarction Prevention Study7 show
that even small increases in HDL-C on statin and fibrate therapy contribute to
risk reduction. In patients with established CAD or who require percutaneous
coronary interventions, low HDL-C is associated with poorer long-term
HDL-C and Atherogenicity
The contention that HDL particles are antiatherogenic is certainly
plausible from a biological standpoint. The most important antiatherogenic
function attributable to HDL particles is likely their ability to engage in
reverse cholesterol transport (RCT),8 the
process by which HDL particles interact with lipid-laden macrophages in the
subendothelial space, promote mobilization and externalization of cholesterol,
and transport cholesterol back to the liver.
A recent elegant clinical investigation demonstrated that
HDL-dependent efflux capacity correlates with risk for CAD in humans.9 HDL particles are important transporters of
micro-messenger RNA that regulate cellular function and also carry a large
variety of proteins, apolipoproteins, sphingolipids, ribonucleic acids and
enzymes that determine HDL particle function.10
In terms of cardiac protection and other beneficial health effects,
HDL particles can reduce lipid oxidation, reverse endothelial dysfunction,
influence platelet activation, decrease inflammation and participate in
systemic insulin sensitization.11,12 HDL is clearly vastly distinct from such atherogenic
lipoproteins as low-density or very low-density lipoproteins.
Niacin and HDL-C
Niacin (or nicotinic acid) is the best drug currently available for
raising serum levels of HDL-C. Niacin binds to cell surface receptors present
in a number of tissues and exerts complex effects on lipid and lipoprotein
production and clearance.13 As monotherapy,
niacin reduced the risk of MI and ischemic stroke by 26% and 24%, respectively,
in studies of patients with CAD.14
In small studies, the combination of niacin and a statin appeared to
provide outsized levels of reduction in risk for CV events.15,16 In the HDL Atherosclerosis
Treatment Study (HATS), the use of high-dose niacin in combination with
simvastatin compared with placebo yielded an 89% relative risk reduction for CV
events and induced modest regression of atherosclerotic plaque based on
quantitative coronary angiography in patients with CAD.16 At baseline, patients treated with combination
therapy had a low-density lipoprotein cholesterol (LDL-C) level of 124 mg/dL,
HDL-C of 34 mg/dL, and triglycerides of 158 mg/dL. Due to the small patient
population of the HATS trial, which randomized approximately 40 patients to
each treatment arm, a larger study was needed to validate or refute these
Niacin in the AIM-HIGH Study
The Atherothrombosis Intervention in Metabolic Syndrome with Low
HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial was
designed to compare the efficacy of statin monotherapy with statinniacin
combination therapy in patients with established CAD.17 The trial enrolled 3,414 participants in the United
States and Canada with a history of cardiovascular disease and randomized
subjects to treatment with either simvastatin alone or in combination with
ezetimibe adjuvant therapy or simvastatin/ezetimibe with extended release
niacin therapy of 1,500 to 2,000 mg daily. The target LDL-C before
randomization was 40 to 80 mg/dL. Baseline characteristics appear in the
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The primary endpoint for AIM-HIGH was a composite defined as time to
first occurrence of any of the following:
- Coronary heart disease death
- Nonfatal MI
- Ischemic stroke
- Hospitalization for acute coronary syndrome
- Symptom-driven coronary or cerebral revascularization
Background therapy for all risk factors (blood pressure, blood
glucose) was rigorous and met the goals set forth in guidelines for high-risk
patients. The addition of niacin to half of the patients did provide
incremental HDL-C elevation and triglyceride reduction. However, the National
Heart, Lung, and Blood Institute (the sponsor of the study) halted the trial
prematurely because continuing was deemed futile after interim analyses showed
no significant difference in adverse outcomes between the 2 groups (249 primary
outcome events [15%] in the simvastatin arm and 262 [15%] in the
simvastatin/niacin arm; hazard ratio 1.053, 97.5% CI: 0.885–1.252;
P =0.561).18 Moreover, investigators
observed an excess hazard for ischemic stroke (28 vs. 12) that was numerically,
though not statistically, significant in the group receiving niacin. No other
studies have suggested that niacin somehow potentiates risk for ischemic
stroke, and certainly concern has been voiced that AIM-HIGH may have been
terminated prematurely despite the rigorous statistical analysis.
The HDL Hypothesis
So, should physicians stop using niacin to treat low serum levels of
HDL-C? Does AIM-HIGH refute the HDL hypothesis? Do the results of AIM-HIGH
refute the findings of other positive studies with niacin?
I believe the answer to all of these questions is “no.” The
patients in AIM-HIGH represent a small fraction of those with CAD typically
encountered in clinical practice. For the most part, these patients were very
aggressively treated, had been on ongoing lipid-lowering therapy, and their
atherogenic lipoprotein burden (LDL-C = 71 mg/dL and non-HDL-C 106 = mg/dL) was
quite low, closely approximating the National Cholesterol Education Program
targets for patients at high risk.19
Patients’ other risk factors were aggressively treated and controlled.
An appropriate interpretation of these data is that the patient
population defined by AIM-HIGH did not benefit from adjuvant niacin therapy,
and at least during the 2.5-year average follow-up period, raising HDL-C
provided no incremental benefit, probably because these patients received such
intensive, comprehensive, long-term risk factor management.
The AIM-HIGH data do not refute the HDL hypothesis or the findings of
the Familial Atherosclerosis Treatment Study,20
HATS16 or the Armed Forces Regression
Study.21 These studies all used different
approaches to lipid modification with combinations of drugs that included
niacin and different inclusion and exclusion criteria and baseline lipid
profiles. Niacin should still be used to help patients attain their risk
stratified NCEP LDL-C and non-HDL-C goals. If high-risk patients have attained
these goals with other drugs despite having a low baseline HDL-C, then,
consistent with AIM-HIGH, niacin adjuvant therapy provides no further
A study larger than AIM-HIGH known as the Treatment of HDL to Reduce
the Incidence of Vascular Events (HPS2-THRIVE) study is still underway and
includes approximately 20,000 patients from the United Kingdom, China and
various Scandinavian countries. HPS2-THRIVE will provide much more needed
information about adjuvant therapy with niacin in a broader spectrum of
patients on statin therapy. Subsequent to the announcement that AIM-HIGH was
being terminated, an interim analysis of the HPS2-THRIVE cohort did not suggest
futility, and the trial remains ongoing.22
The capacity of HDL particles to induce coronary atherosclerotic
disease regression has been shown in a number of studies that used HDL infusion
therapy.23,24 Much insight
into the role of HDL elevation in preventing and managing CAD will be provided
by studies using the cholesterol ester transfer protein inhibitors, such as
anacetrapib and dalcetrapib. It is far too early to abandon efforts to raise
HDL in order to reduce residual risk in patients on statin therapy.
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MC, et al. Shotgun proteomics implicates protease inhibition and complement
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18. National Institutes of Health. NIH stops clinical trial on
combination cholesterol treatment [press release].
Accessed November 30, 2011.
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Accessed November 30, 2011.
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